Congenital hyperinsulinism and the surgeon: lessons learned over 35 years.

BACKGROUND/PURPOSE: Congenital hyperinsulinism induces severe and unremitting hypoglycemia in newborns and infants. If poorly controlled, seizures and irreversible brain damage may result. Subtotal (<95%) or near-total (95% to 98%) pancreatectomy have been performed for glycemic control in babies who do not respond to aggressive medical therapy. Because hypoglycemia often persists after subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To define the effect of more or less extensive pancreatectomy on the management and outcome of refractory congenital hyperinsulinism, the authors examined our single institutional experience. METHODS: The records of children treated between 1963 and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were reviewed. Outcome parameters included glycemic response to surgery, need for reresection, surgical morbidity, surgical and long-term mortality, and development of diabetes mellitus (DM). A complete response was defined as discharge to home on no glycemic medications, no continuous feedings, and without DM. Histological reports were reviewed and categorized as either diffuse or focal disease. RESULTS: Of 101 children treated for congenital hyperinsulinism during this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed a complete response, occurring in 50% of patients having > or = 95% pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16). The remaining three babies had local excision of a solitary focal lesion, and each showed a complete response. Histopathology showed diffuse islet abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A complete response was observed for 82% of focal but only 33% of diffuse lesions. Eight patients (15%) required reresection for persistent hypoglycemia, seven having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3) occurring before 1975. DM developed in seven children (14%), each having diffuse lesions, and was independent of resection type. CONCLUSION: Because euglycemia is more readily restored, and because the risks for surgical complications and DM do not appear increased, the authors recommend 95% pancreatectomy as the initial procedure of choice for newborns and infants with congenital hyperinsulinism.

Prognostic value of quantitative pathologic features and DNA content in individual patients with stage I endometrial adenocarcinoma.

The prognostic value of clinical features, qualitative and quantitative pathologic characteristics and steroid receptor incidence was evaluated in 50 patients with Stage I endometrial adenocarcinoma. It turned out that many of these features were prognostically important. Estrogen receptor content was not significantly associated with prognosis in our material, but patients with progesterone receptor positive lesions had a better survival than those in which the tumors were progesterone receptor negative. Multivariate analysis also clarified that only three features in combination had independent significance: mean shortest nuclear axis, DNA index, and depth of myometrial invasion (in sequence of decreasing importance). The prognostic rule consisting of these features overshadowed the value of all other features investigated. The overriding prognostic value of this highly reproducible rule was clear from the complete separation of 27 survivors and six nonsurvivors in the learning set of 33 patients. In an independent test set, all three nonsurvivors and 13 of the 14 survivors were correctly classified, thus confirming the accuracy and reliability of the developed rule to predict the outcome of future patients with Stage I endometrial adenocarcinoma.

Protein/creatinine ratio in the assessment of proteinuria during pregnancy.

Since the nature and the level of urinary protein excretion have considerable clinical implications in the course of pregnancy, the early detection of even minor degrees of hyperproteinuria is important. Quantitation of 24-h urinary protein excretion is the only definite method of establishing the presence of hyperproteinuria, but this method shows practical failures particularly in an outpatient setting. Dipstick analysis as a screening for hyperproteinuria also lacks reliability, since the normal rate of protein excretion in primigravid pregnancy has recently been shown to be less that 150 mg per day. In this study, therefore, we propose the determination of the protein/creatinine ratio in a single voided urine sample, obtained during normal daylight activity, as a screening test for hyperproteinuria during pregnancy which can replace the quantitation of 24-h urinary protein excretion.

The influence of spontaneous breech delivery on the integrity of the central nervous system of the newborn (a prospective study).

The effect of breech delivery on the condition of the newborn infant was studied in a population of 48 consecutive, mature, newborn infants delivered spontaneously and having birth weights between the 5th and 95th percentiles for gestational age. The integrity of the central nervous system of all infants was assessed semiquantitatively by Prechtl's method of neurological examination. The results were compared to those obtained in a previous study of a similar group of infants born in vertex presentation. In contrast to retrospective studies, no differences in neurologic condition were found blood and neurological score, demonstrated previously in infants born in vertex presentation, was found in the breech infants.

A quantitative structural model of the testis of fertile males with normal sperm counts.

The morphology of testicular biopsies of 8 healthy fertile men with proven normal sperm counts was studied using stereological techniques. Quantitative estimations were made of different cellular compartments in the testicular biopsies. The experimental errors of observation, homogeneity of the section, accuracy of the measurements and errors caused during the preparation of the sections were studied. A stereological model of the human testis comprising all compartments was designed. The present observations on the stereological parameters were compared with the results in literature; generally a good agreement was found. This stereological model enabled the authors to establish the quantitative correlations that exist between the separate compartments of the human testis. The tubular length density was positively correlated with the tubular surface density. The tubular surface density showed a negative correlation with the volume density of the germinal cell nuclei. The tubular volume density showed a negative correlation with the volume density of the Leydig cells. The intra-tubular volume density correlated negatively with the volume density of the Leydig cells and with the volume density of the remaining extra-tubular tissue. The intra-tubular tissue density correlated negatively with the volume density of the intra-tubular space.

Postpartum resolution of glomerular changes in edema-proteinuria-hypertension gestosis.

Complete resolution of glomerular changes in toxemia of pregnancy has been reported to occur as early as 4 weeks postpartum, whereas their persistence for as long as 2 years in some instances has been noted. However, the mechanism of resolution remains obscure. Percutaneous renal biopsy was performed in 22 patients between 10 and 14 days after delivery. These women fulfilled the criteria for toxemia of pregnancy (edema-proteinuria-hypertension gestosis). Biopsy specimens were examined, using light, immunofluorescence and electron microscopy. Semithin sections were studied in view of greater reliability and better relation with further electron microscopic studies. A diffuse increase in mesangial cellularity and matrix was seen in all glomeruli with varying intensity, compatible with mesangium activity, more than endothelial proliferation. So-called capillary occlusions by endothelial swelling were not observed in the biopsies taken 10 days after delivery, but expulsed mesangial cytoplasm could be observed incidentally in the capillary lumen. This phenomenon may explain the wrong interpretation of paraffin sections studied by light microscopy. The presence of immunoglobulins in the glomeruli, seen by immunofluorescence, seems to be nonspecific trapping. In view of experimental studies of mesangium function in macromolecular uptake and processing, it is possible that resolution of the characteristic renal lesions in toxemia is promoted by mesangium activity.

Age at menarche and menopause of uterine cancer patients.

An investigation was undertaken of the ages at menarche and at menopause of cervical and endometrial cancer patients for the years 1950-55 and 1960-65. Analysis of the ages at menarche in relation to the year of birth did not show a difference between the uterine cancer groups, whereas the age at menopause did show such a difference. The menopause occurred later in the endometrial than in the cervical cancer group. There was an earlier mean age at menarche and a later mean age at menopause per decade. Therefore, the menopause seems a constitutional factor involved in the development of endometrial cancer and perhaps also cervical cancer.

Quantitative morphology of the placenta. III. The growth of the placenta and its relationship to birth weight.

The relationship of placental components to birth weight was investigated by stereology. 37 placentas from nonpathological pregnancies delivered after a period of 224-303 days of amenorrhea were examined. The umbilical cord was clamped immediately after birth. The ratios of the volume, the surface, the length of the villous vessels and the surface of the villi with birth weight showed a decrease after 277 days of amenorrhea. In contrast to this decrease, the ratio of the volume of the trophoblast with birth weight seems to increase. No difference could be found for the ratios of the placental volume (placental index), the volume of the villous tissue, the volume of the intervillous space and the volume of the nonfunctional tissue with birth weight. These ratios reveal a quantitative morphological base for the clinical experience that postmature fetuses are at a higher risk through deterioration of the placenta.

Quantitative morphology of the placenta. II. The growth of the placenta and the problem of postmaturity.

The morphological changes in the placenta concomitant with the transition from maturity to postmaturity were investigated by stereology under early clamping of the umbilical cord. 37 placentas from nonpathological pregnancies delivered after a period of 224-303 days of amenorrhea were examined. It appeared that after 267-288 days of amenorrhea, 8 out of 9 placental components showed no further growth and even showed regression. Only the volume of the trophoblast continued to grow in postmaturity. It is suggested that during postmaturity the villous capacity to produce steroids is continuing at a normal rate (as judged by the increase of the volume of the trophoblast), whereas the capability to transfer is deteriorating (as testified by the decreasing surface of the trophoblast).

Fetal breathing movements in the normal and growth-retarded human fetus: a multiscan/M-mode echofetographic study.

52 women were examined, between the 25th and 40th wk of pregnancy, during the day-time, by the echographic multiscan/M-mode technique. Definitions of normal fetal breathing movements and singultus fetalis movements were determined. In normal pregnancies fetal breathing movements occurred during 12-19% of the total observation time before the 39th wk of pregnancy but only during 6-9% of the observation time in the 39th or 40th wk. In low birth weight pregnancies fetal breathing movements occurred during 8-13% of the total observation time, and the incidence was the same before and after the 39th wk. Singultus fetalis movements occurred in normal and low birth weight pregnancies.

Marriage and childbearing in relation to cervical cancer.

In order to assess any correlation between cervical cancer and age at marriage and childbearing, matched control groups were formed. From the comparison it appears that cervical cancer patients are more likely to be married and to have married at an earlier age than control women. In the same age groups at marriage there was no difference in the number of children between the cervical cancer patients and the control women. It appeared that cervical cancer patients had their first child earlier than control women. There were more illegitimate children in the cervical cancer groups than in the control groups, but after the wedding date there were no differences between the cervical cancer groups and the control groups in the time between the wedding date and the date of birth of the first child. The data show that after pregnancy or childbirth, in particular at an early age, there is a greater risk of getting a cervical cancer. By contrast, nulliparous married women seem to have a low risk of cervical cancer.

The fetal autonomic nervous system, the fetal heart rate and the beat-to-beat irregularity.

In the exteriorized fetal lamb an experimental study on the influence of the fetal autonomic nervous system upon the heart rate pattern is described by means of blockage of the cholinergic, alpha-adrenergic and beta-adrenergic system. The alpha-adrenergic system proved to have no effect upon heart rate. The beta-adrenergic system had a positive chronotropic effect and the parasympathetic system had a negative chronotropic effect. Beat-to-beat irregularity was independent of a functional alpha-adrenergic system, but at a high basic heart rate disappeared completely after cholinergic blockage and at a low rate after beta-adrenergic blockage. It is concluded that most probably the beat-to-beat irregularity is the result of the competition of the enhancing influence of the beta-adrenergic system and the inhibiting influence of the cholinergic system on fetal heart rate.